2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of lithium diisopropylamine (1.8 M, 4.96 mL, 8.92 mmol) in THF (8 mL) was placed under an Argon atmosphere and was cooled to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1200 mg, 3.57 mmol) in THF (8 mL) was cooled to −78° C. and added drop wise to the LDA solution. The reaction mixture was stirred 30 minutes at −78° C. The product of Step 1 (625 mg, 3.57 mmol) in THF (8 mL) was added drop wise and the reaction was allowed to warm to room temperature overnight. The mixture was quenched with brine, diluted with ethyl acetate. The organics were washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes) to afford 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfinamide (1.10 g, 2.140 mmol, 60.0% yield). MS ESI: [M+H]+ m/z 512.1. to warm to room temperature overnight The mixture was quenched with brine diluted with ethyl acetate The organics were washed with saturated NaHCO3 dried (Na2SO4) filtered concentrated The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxetan-3-one (600 mg, 8.33 mmol) and 2-methylpropane-2-sulfinamide (1.01 g, 8.33 mmol) in tetrahydrofuran (14 mL), titanium ethoxide (3.45 mL, 16.65 mmol) was added. The mixture was stirred at 50° C. overnight. The reaction mixture was poured over brine. The suspension was filtered through celite and washed with ethyl acetate. The solution was partitioned between ethyl acetate and brine. The organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (0-70% ethyl acetate in hexanes) to afford 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (692 g, 3.20 mmol, 38% yield) as a clear oil. MS ESI: [M+H]+ m/z 176.1. The suspension was filtered through celite washed with ethyl acetate The solution was partitioned between ethyl acetate and brine The organics were dried (Na2SO4) filtered concentrated The residue was purified by column chromatography on silica (0-70% ethyl acetate in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium in hexanes (1.65M, 4.92 mL) was added dropwise to a solution of 1,4-dibromobenzene (2.05 g) in THF (25 mL) dropwise over the course of 30 min at −78° C. The resulting mixture was stirred at the same temperature for 1 h. To the mixture was added a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (1.02 g) in THF (5 mL) dropwise over the course of 30 min at −78° C. The reaction mixture was stirred for an additional 30 min. at −78° C. then allowed to warm to room temperature. After being stirred for 1 h at room temperature, the reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes then 5% methanol in ethyl acetate) gave the product (1.85 g, 96%). 1HNMR (CDCl3) 400 MHz δ: 7.55 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.16 (d, J=6.9 Hz, 1H), 5.06 (d, J=6.9 Hz, 1H), 5.02 (d, J=6.9 Hz, 1H), 4.94 (d, J=6.9 Hz, 1H), 4.05 (br s, 1H), 1.22 (s, 9H). LCMS: 332, 334 [M+H]. The reaction mixture was stirred for an additional 30 min. at −78° C. After being stirred for 1 h at room temperature the reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution The aqueous layer was extracted with ethyl acetate The combined organic layer was washed with saturated sodium bicarbonate solution The organics were dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by column chromatography (50-100% ethyl acetate in hexanes

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methyl-2-propanesulfinamide (1.47 g) and 3-oxetanone (0.85 mL) in THF (24 mL) was added Ti(OEt)4 (5.34 mL) dropwise over the course of 15 minutes at room temperature. After being stirred at 60° C. for 18 h, the reaction mixture was quenched by the rapid addition into ice cooled saturated sodium bicarbonate aqueous solution. The suspension was filtered through glass fiber filter paper and the cake was washed with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (1.02 g, 48%). 1HNMR (CDCl3) 400 MHz δ: 5.80 (ddd, J=15.6, 4.1, 2.3 Hz, 1H), 5.66 (ddd, J=15.6, 4.1, 2.3 Hz, 1H), 5.52-5.41 (m, 2H), 1.27 (s, 9H). the reaction mixture was quenched by the rapid addition into ice cooled saturated sodium bicarbonate aqueous solution The suspension was filtered through glass fiber filter paper the cake was washed with ethyl acetate The filtrate was washed with saturated sodium bicarbonate solution The organics were dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by column chromatography (10-100% ethyl acetate in hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of lithium diisopropylamine (1.8 M, 4.96 mL, 8.92 mmol) in THF (8 mL) was placed under an Argon atmosphere and was cooled to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1200 mg, 3.57 mmol) in THF (8 mL) was cooled to −78° C. and added drop wise to the LDA solution. The reaction mixture was stirred 30 minutes at −78° C. The product of Step 1 (625 mg, 3.57 mmol) in THF (8 mL) was added drop wise and the reaction was allowed to warm to room temperature overnight. The mixture was quenched with brine, diluted with ethyl acetate. The organics were washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes) to afford 2-methyl-N-{3-[5-(3-methyl-5-[[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl]propane-2-sulfinamide (1.10 g, 2.140 mmol, 60.0% yield). MS ESI: [M+H]+ m/z 512.1. to warm to room temperature overnight The mixture was quenched with brine diluted with ethyl acetate The organics were washed with saturated NaHCO3 dried (Na2SO4) filtered concentrated The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxetan-3-one (600 mg, 8.33 mmol) and 2-methylpropane-2-sulfinamide (1.01 g, 8.33 mmol) in tetrahydrofuran (14 mL), titanium ethoxide (3.45 mL, 16.65 mmol) was added. The mixture was stirred at 50° C. overnight. The reaction mixture was poured over brine. The suspension was filtered through celite and washed with ethyl acetate. The solution was partitioned between ethyl acetate and brine. The organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (0-70% ethyl acetate in hexanes) to afford 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (692 g, 3.20 mmol, 38% yield) as a clear oil. MS ESI: [M+H]+ m/z 176.1. The suspension was filtered through celite washed with ethyl acetate The solution was partitioned between ethyl acetate and brine The organics were dried (Na2SO4) filtered concentrated The residue was purified by column chromatography on silica (0-70% ethyl acetate in hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred for 30 min at −78° C. before a solution of 2-methyl-n-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7) (500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at −78° C. The reaction solution was stirred for an additional 30 min at −78° C. before being warmed to 22° C., and then was quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with anhydrous sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (EI): m/e=261.0 [M+H]+. was added dropwise at −78° C before being warmed to 22° C. was quenched with saturated aqueous ammonium chloride solution The crude reaction mixture was then partitioned between water and ethyl acetate The aqueous layer was further extracted with ethyl acetate The combined layers were washed with saturated aqueous sodium chloride solution the washed solution was dried with anhydrous sodium sulfate evaporated down to dryness The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes flushing with 10% methanol-dichloromethane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred for 30 min at −78° C. before a solution of 2-methyl-n-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7) (500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at −78° C. The reaction solution was stirred for an additional 30 min at −78° C. before being warmed to 22° C., and then was quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with anhydrous sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (EI): m/e=261.0 [M+H]+. was added dropwise at −78° C before being warmed to 22° C. was quenched with saturated aqueous ammonium chloride solution The crude reaction mixture was then partitioned between water and ethyl acetate The aqueous layer was further extracted with ethyl acetate The combined layers were washed with saturated aqueous sodium chloride solution the washed solution was dried with anhydrous sodium sulfate evaporated down to dryness The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes flushing with 10% methanol-dichloromethane)